The long-term goal of the project is to develop a tumor-specific therapeutic approach to reduce the mortality of small cell lung cancer (SCLC). SCLC metastasizes at an early stage, and most cases relapse and become resistant to current therapies. The 5-year survival is only 5 percent. It causes approximately 40,000 deaths/y in the US. However, SCLC also has many molecular targets that could be used for tumor-targeted therapy. Our strategy is to target Bcl-2 family anti-apoptotic genes and telomerase, both of which are over-expressed in >90% of SCLC patients in their tumor, but not normal, tissues. Over-expression of these genes is directly related to the metastasis, and therapeutic resistance of SCLC. We hypothesize that if an optimal delivery system can efficiently deliver a tumor-specific pro-apoptotic gene systemically (e.g., by i.v.), the expressed gene product can either kill the tumor cells directly or block the function of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL) that contribute to resistance, therefore, sensitizing them for chemotherapy, such that a low-dose of a chemotherapeutic agent will selectively kill the sensitized tumor cells in primary and metastatic tumors, but not normal cells. The combination therapy should have minimal systemic toxicity and higher efficacy than either modality alone. Our aims are: 1. To develop a SCLC tumor-specific formulation. We will encapsulate a two-polymer-condensed DNA, an active transfection unit, into a stabilized cationic liposome. The tumor-specific gene expression system will include a Bcl-2 family pro-apoptotic gene, bik or bax, driven by the tumor-specific promoter, an activity enhanced human telomerase reverse transcriptase promoter (hTRpG). The formulation will be optimized by stability and pharmacokinetics studies. 2. To characterize the toxicology and antitumor activity of the combination therapeutic approach. We will study the toxicity of this nonviral gene delivery system and the combination therapy by quantifying pro-inflammatory cytokines and histopathological changes in mice. The myelo- and nephro-toxicity caused by Cisplatin will be also determined. We will select chemo-sensitive and -resistant human SCLC cell lines to make metastatic xenografts in nude mice, and then test the antitumor activity of the gene/chemo combination therapy. [unreadable] [unreadable] [unreadable]